X-133753688-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004484.4(GPC3):c.826G>A(p.Gly276Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,209,642 control chromosomes in the GnomAD database, including 1 homozygotes. There are 41 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G276C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., 20 hem., cov: 22)

Exomes 𝑓: 0.00010 ( 1 hom. 21 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: 3.10

Variant links:

Genes affected

GPC3 (HGNC:4451): (glypican 3) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

GPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036491454).

BP6

Variant X-133753688-C-T is Benign according to our data. Variant chrX-133753688-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95100.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, not_provided=1, Uncertain_significance=1, Likely_benign=3}. Variant chrX-133753688-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4 linkuse as main transcript	c.826G>A	p.Gly276Ser	missense_variant	3/8	ENST00000370818.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8 linkuse as main transcript	c.826G>A	p.Gly276Ser	missense_variant	3/8	1	NM_004484.4	P1	P51654-1

Frequencies

GnomAD3 genomes

AF:

0.000732

AC:

AN:

112075

Hom.:

Cov.:

AF XY:

0.000584

AC XY:

AN XY:

34249

show subpopulations

Gnomad AFR

AF:

0.00240

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000474

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.000246

AC:

AN:

183233

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

67765

show subpopulations

Gnomad AFR exome

AF:

0.00243

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000102

AC:

112

AN:

1097513

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

362883

show subpopulations

Gnomad4 AFR exome

AF:

0.00307

Gnomad4 AMR exome

AF:

0.000398

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000731

AC:

AN:

112129

Hom.:

Cov.:

AF XY:

0.000583

AC XY:

AN XY:

34313

show subpopulations

Gnomad4 AFR

AF:

0.00239

Gnomad4 AMR

AF:

0.000473

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000374

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00130

Alfa

AF:

0.0000237

Hom.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	This variant is associated with the following publications: (PMID: 24728327) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 19, 2022

- -

Wilms tumor 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.0

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.;.

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.036

T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.5

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.2

D;D;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

D;D;.

Sift4G

Uncertain

0.020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.17

MVP

0.84

MPC

0.60

ClinPred

0.11

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.69

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over